Sphingomyelin(d35:1) as a novel predictor for lung adenocarcinoma recurrence after a radical surgery: a case-control study

Abstract

Background: To improve the postoperative prognosis of patients with lung cancer, predicting the recurrence highrisk patients is needed for the efficient application of adjuvant chemotherapy. However, predicting lung cancer recurrence after a radical surgery is difficult even with conventional histopathological prognostic factors, thereby a novel predictor should be identified. As lipid metabolism alterations are known to contribute to cancer progression, we hypothesized that lung adenocarcinomas with high recurrence risk contain candidate lipid predictors. This study aimed to identify candidate lipid predictors for the recurrence of lung adenocarcinoma after a radical surgery. Methods: Frozen tissue samples of primary lung adenocarcinoma obtained from patients who underwent a radical surgery were retrospectively reviewed. Recurrent and non-recurrent cases were assigned to recurrent (n = 10) and non-recurrent (n = 10) groups, respectively. Extracted lipids from frozen tissue samples were subjected to liquid chromatography-tandem mass spectrometry analysis. The average total lipid levels of the non-recurrent and recurrent groups were compared. Candidate predictors were screened by comparing the folding change and P-value of t-test in each lipid species between the recurrent and non-recurrent groups. Results: The average total lipid level of the recurrent group was 1.65 times higher than that of the non-recurrent group (P < 0.05). A total of 203 lipid species were increased (folding change, ≥2; P < 0.05) and 4 lipid species were decreased (folding change, ≤0.5; P < 0.05) in the recurrent group. Among these candidates, increased sphingomyelin (SM)(d35:1) in the recurrent group was the most prominent candidate predictor, showing high performance of recurrence prediction (AUC, 9.1; sensitivity, 1.0; specificity, 0.8; accuracy, 0.9). Conclusion: We propose SM(d35:1) as a novel candidate predictor for lung adenocarcinoma recurrence. Our finding can contribute to precise recurrence prediction and qualified postoperative therapeutic strategy for lung adenocarcinomas. Trial registration: This retrospective study was registered at the UMIN Clinical Trial Registry (UMIN000039202) on 21st January 2020.

Cell surface sphingomyelin: key role in cancer initiation, progression, and immune evasion

“…Fourth, high SM synthase expression and aberrant SM contents were associated with breast cancer progression and metastasis [ 60 ]. Fifth, increased SM content in frozen tissue samples of primary lung adenocarcinoma obtained from patients who underwent radical surgery was the most reliable indicator of recurrence, i.e., of degree of malignancy [ 61 ]. Six, low levels of surface membrane-associated neutral sphingomyelinase (nSMase)-2, responsible for SM hydrolysis, were associated with early recurrence of hepatic cell carcinoma after surgery [ 62 ].…”

Decreased sphingomyelin (t34:1) is a candidate predictor for lung squamous cell carcinoma recurrence after radical surgery: a case-control study

“…Lipid extraction was performed as reported previously [ 18 ]. Briefly, we measured each tissue weight using a Sartorius analytical lab balance CPA224S (Sartorius AG, Göttingen, Germany) (Additional file 1 , Supplemental Table 1).…”

“…Survival under oxidative stress and energy stress are promoted by membrane saturation and lipid droplet formation, respectively [ 14 , 15 ]. Furthermore, some lipids have been suggested as prognostic factors in several cancer types [ 16 – 18 ]. In our previous study, increased sphingomyelin (SM)(d35:1) in lung adenocarcinoma (ADC) demonstrated excellent recurrence prediction ability (superior to histopathological factors) and was considered as a promising candidate predictor for recurrence after radical surgery [ 18 ].…”

“…Furthermore, some lipids have been suggested as prognostic factors in several cancer types [ 16 – 18 ]. In our previous study, increased sphingomyelin (SM)(d35:1) in lung adenocarcinoma (ADC) demonstrated excellent recurrence prediction ability (superior to histopathological factors) and was considered as a promising candidate predictor for recurrence after radical surgery [ 18 ]. The prediction ability of SM(d35:1) was considered excellent due to its high objectivity and is expected to overcome the limitation of histopathological prognostic factors in recurrence prediction.…”

“…The prediction ability of SM(d35:1) was considered excellent due to its high objectivity and is expected to overcome the limitation of histopathological prognostic factors in recurrence prediction. Following this result, identification of lipid candidate predictors for recurrence in lung squamous cell carcinomas (SQCCs), which is the major histological subtype of NSCLC behind only ADC, was anticipated [ 18 ].…”